Fertility and sexual dysfunction in young male cancer survivors

Abstract Background Newly emerging serious post‐treatment complications among young male cancer survivors involve fertility and sexual function, preventing them from pursuing a normal family life. Methods We studied and summarized published studies that assess the relationship between cancer treatments and reduced spermatogenesis or sexual dysfunction. Main findings Infertility often occurs because of anticancer therapies that impair spermatogenesis. While some patients postremission functionally recover fertility, others experience a decreased sperm count and azoospermia. Fertility‐preserving modalities are currently being promoted worldwide to preserve spermatogenesis following cancer therapy. Patients who can ejaculate and have sperm in their semen should cryopreserve semen. However, for patients who have never ejaculated before puberty or in whom spermatogenesis has not been established, testis biopsy is performed to collect and preserve sperm or germ cells. Fertility preservation is gaining popularity and requires continuous information dissemination to oncologists and cancer treatment professionals. Furthermore, male sexual dysfunction predominantly involves erectile dysfunction and ejaculation disorder. Conclusion Although preventive and therapeutic methods for these disorders have been established within urology, patients and medical professionals in other fields remain uninformed of these advances. Therefore, dissemination of information regarding fertility preservation techniques should be accelerated.

Young cancer patients may be afflicted in the long term because of late complications of treatment, even if the disease is cured, and the impairment of fertility and sexual function is just one of the sequelae. Some patients may forgo marital or other intimate partnerships due to sexual dysfunction or infertility, and others may be forced to make major changes to their life plans. Benedict et al. conducted a survey of 43 men and women who survived cancer during their adolescence and young adult (AYA) generation about their fertility; half of the men reported uncertainty regarding their fertility status. 4 In a study involving survivors of cancer treatment in the AYA generation, 48.8% had impaired sexual function and intimate relationships 1 year after treatment; even after 2 years, 70% of survivors continued to experience these effects. 5 As the treatment outcomes of young cancer patients have improved, it is important to communicate information regarding novel treatment and prevention methods for these sequelae to provide them hope for the future.

| DECRE A S ED FERTILIT Y DUE TO C AN CER TRE ATMENT
Disorders of spermatogenesis after chemotherapy or radiation therapy are among the most problematic sequelae of cancer treatment, and 15%-30% of male cancer survivors lose their fertility. 6 Walsile-Masker et al. conducted a questionnaire survey of 1622 male cancer survivors and 264 siblings on post-cancer infertility; the incidence of infertility in the cancer survivor cohort was 46%, and that in siblings was 17.5% (relative risk (RR) = 2.34, 95% confidence interval [CI] 1.88-3. 70, p < 0.001). Most causes of infertility are due to the gonadotoxic effects of chemotherapy or radiation therapy. 7

| Impact of cancer treatment on spermatogenesis
Spermatogonia are highly sensitive to the cytotoxic effects of radiation and anticancer drugs. In particular, agent sensitivity increases during differentiation. 8 Later-stage germ cells, on the other hand, are relatively resistant to cell-killing effects. Therefore, although the number of spermatogonia decreases immediately after cancer treatment, spermatogenesis from later-stage germ cells (spermatocytes and spermatids) continues. A study indicated that the sperm count did not change significantly immediately after the start of treatment but dropped sharply from 1/10 to 1/100 1-2 months after the start of treatment, and azoospermia may occur 12 weeks after treatment, depending on the drug and dosage. 9 In the case of a drug with a low cytotoxic effect, the sperm count normalizes again about 12 weeks after the end of chemotherapy.
In contrast, in treatments with high cell-killing effects, the pros and cons of sperm function recovery and the extent and time of recovery, depend on the number of stem cells remaining after treatment. 9 The number of surviving spermatogonia depends on the type of drug, regimen, and dose. For example, alkylating agents are highly toxic to the testes, and with cyclophosphamide, azoospermia is prolonged at a total dose of 19 g/m 2 for a single agent and 7.5 g/m 2 or more for a combination of multiple agents. 10 Ifosfamide increases the damage at total doses of 42 g/ m 2 and above. 11 Cisplatin increases the risk of azoospermia at doses >400 mg/m 2 . 8 Magelssen et al. administered cisplatin-based chemotherapy to 170 germ cell tumor patients who had normozoospermia before treatment and investigated semen findings at least 1 year after treatment; 64% of patients had normozoospermia, 16% had oligozoospermia, and 20% showed azoospermia. 12 In the case of radiation therapy, spermatocytes begin to decrease approximately 21 weeks after a single irradiation of 0.2-4 Gy, and differentiation into spermatocytes also decreases. 13,14 In general, the sperm count begins to decrease when the irradiation dose to the testes is 0.15 Gy or higher, and reversible azoospermia is exhibited at 0.35-0.5 Gy. Nadir with decreased sperm count occurs 4-6 months after the end of treatment and takes 10-18 months to recover fully. If the dose increases, the recovery time is extended, but the original sperm count may not be re-established in cases undergoing irradiation of 1.2 Gy or more. 11,15 Only 15% of patients recover fertility with a single dose of 10 Gy, 9 and 95% present with Sertoli cell-only syndrome when the dose exceeds 16-18 Gy. 16 Fractionated irradiation is effective for cancer treatment; however, although damage to the irradiated area is reduced, damage to the testes is significant. Cumulative doses to the testes above a total of 2.5 Gy can lead to irreversible azoospermia. 11,15 The combined damage of chemotherapy and radiation therapy is significant, with 83% of patients presenting with permanent azoospermia due to total body irradiation and cyclophosphamide administration prior to stem cell transplantation in leukemia. 17 Based on these findings, the American Society of Clinical Oncology (ASCO) classifies the risks to sperm function in anticancer drugs and radiation therapy into four stages (Table 1). 18 Treatments classified as high risk may prolong azoospermia, and it is advisable to preserve sperm before treatment.
In recent years, cancer treatment with molecular target agents, such as tyrosine kinase inhibitors (TKIs), has been increasing. TKIs suppress cancer proliferation by targeting molecules present on cells and suppressing cell proliferation. Currently, the risk classification of the ASCO guidelines still states that the adverse effects on spermatogenesis are unknown. 18 However, there are reports that TKI treatment may lead to a risk of decreased fertility; hence, data needs to be collected in the future.

| Recovery of fertility after cancer treatment
As mentioned above, recovery of spermatogenesis after cancer treatment depends on the number of surviving spermatogonia. 9 If spermatogonia do not remain after treatment with a highly celllethal drug or high dose, azoospermia occurs, and even if spermatogonia remain, it may take several years for genesis to recover.
Even in a moderate-risk chemotherapy regimen, the time to recovery will be delayed if the dose and number of courses are high. Suzuki  was extended as the number of cycles increased. No patients in the group who received more than 5-6 courses of BEP therapy recovered their spermatogenesis within 2 years. 19 Martinez et al. reported that it takes approximately 1 year after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) therapy and 2 years after cyclophosphamide, hydroxydaunorubicin (adriamycin), oncovin (vincristine), prednisone/mechlorethamine, oncovin (vincristine), procarbazine, prednisone-adriamycin, bleomycin, vinblastin (CHOP/MOPP-ABV) therapy to recover to pretreatment sperm count levels in patients with malignant lymphoma. 20 Similarly, sperm count can be recovered at low doses with radiation therapy, but it takes 7 months to recover after 1 Gy irradiation and 24 months after 6 Gy. 9 Some young cancer survivors are concerned about sperm chromosomal abnormalities and DNA fragmentation, because this may increase the rate of malformation in their children. In the case of testicular cancer, two or more courses of BEP therapy increase the proportion of sperm with chromosomal aneuploidy; however, this effect diminishes after 24 months. 21 In malignant lymphoma, the proportion of sperm with aneuploidy is higher than before treatment up to 3 months after treatment with ABVD and up to 12 months after treatment with CHOP but then decreases. 20 Thomson et al. compared semen analyses and sperm DNA fragmentation rates of male cancer survivors who underwent cancer treatment in childhood with those of a normal control group. Eleven of the 33 cancer survivors had azoospermia, and the remaining patients also had decreased sperm counts, but the DNA fragmentation rate was not significantly different from that of the normal control group. 22 Sperm DNA fragmentation was also measured before and after treatment in patients with testicular cancer who received chemotherapy and radiation therapy. It was demonstrated that the fragmentation rate increased 6 months after treatment, but there was no significant difference, and it returned to pretreatment levels in about 1 year. 23  Note: High risk: prolonged/permanent azoospermia common after treatment; intermediate risk: prolonged/permanent azoospermia is not common after treatment but can occur; low risk: treatments typically cause only temporary damage to sperm production; very low risk: no effect on sperm production.

| Cryopreservation of sperm or testicular tissue
Cryopreservation of sperm or testicular tissue is the most prevalent fertility-preserving treatment modality for men. The European Society of Human Reproduction and Embryology Task Force designed a cryopreservation algorithm for the preservation of sperm and testicular tissue in prepubertal and adolescent men at risk of loss of fertility ( Figure 1). 27 Sperm cryopreservation is performed in men after puberty if ejaculation is possible. If the patient has difficulty ejaculating or has severe oligospermia or azoospermia, testicular biopsy should be performed, and the mature or immature testis protocol should be selected depending on the presence or absence of sperm. 27 Testicular biopsy for cancer patients is done to look for sperm in the testes. The method is the same as the testicular sperm extraction (TESE) performed on azoospermia patients and is called onco-TESE. The sperm retrieval rate is about 50%-60%. 28 Patients who have never masturbated are recommended to try using a vibrator or devices, such as those facilitating electric ejaculation, before proceeding to testicular biopsy. 29 26 Pubertal patients are first tested for semen, and the storage protocol is performed if the semen contains enough storable sperm. Patients who are unable to produce sperm (including those who cannot ejaculate) or those with oligozoospermia or azoospermia undergo testicular biopsy (Onco-TESE). Intraoperative analysis is performed on the tissues obtained through biopsy, and any sperm detected are stored (mature testis protocol). The immature testis protocol is a method of cryopreserving tissues that contain sperm-like cells (spermatogonia to spermatids). Since there is a high possibility that there are no sperm in the tissue, cryopreservation is expected with the hope that future medical advances will enable the differentiation of sperm-like cells (germ cells) into sperm cells. In prepubertal patients, the tissue is collected and cryopreserved on the premise that masturbation is not possible (immature testis protocol).

| S E XUAL DYS FUN C TI ON OF C AN CER SURVIVOR S
Although not as prevalent as the potential decline in fertility after cancer treatment, the decline in sexual function of cancer survivors is also a serious problem. A 2009 study in the United States found that 49% of male cancer survivors had erectile dysfunction (ED) after treatment, and 30% had orgasm or ejaculation problems. 39 however, investigative logistic analysis indicated that retroperitoneal lymph node dissection (RPLND) was not a contributing factor toward sexual dysfunction. 53 The frequency of patients with a SHIM score of 17 or less was found to decrease over time after surgery.
In their reports, nerve amputation was unlikely to be the cause of the ED. 53 ED is also thought to be caused by a change in body image and a loss of self-confidence as a man. 54 Other factors that cause ED include radiation of ≥10 Gy and spinal surgery. 41  Brachytherapy for prostate cancer may also cause EjD. 58 Hypogonadism can be caused by cranial radiation or irradiation of the testes and leads to anemia, muscle and bone mass loss, and menopausal symptoms. Damage to the pituitary gland due to cranial radiation leads to impaired gonadotropic secretion, and 2/3 of patients who receive cranial radiation have symptoms of hypogonadism. 59 Although less sensitive than germ cells, Leydig cells are also damaged by radiation.
When the total pelvic radiation dose is 4 Gy or more, molecular changes can occur, 60 and if the dose exceeds 20 Gy, androgen supplementation might be needed in the future. 61 In addition, TKI imatinib is said to damage Leydig cells and cause a decrease in testosterone production. 9 Besides radiation therapy to the brain, immune checkpoint inhibitors, such as nivolumab, may cause pituitary inflammation and may reduce gonadotropin secretion and subsequent testosterone production. That is, it causes hypogonadotropic hypogonadism, which in turn leads to sexual dysfunction and impairment of spermatogenesis. 62

| Measures and treatments for sexual dysfunction in cancer survivors
Prevention and treatment are required under these conditions.
A nerve-sparing surgical approach can be employed in prostate cancer surgery to prevent ED. Bilateral nerve-preserving therapy is known to better preserve sexual function when compared to unilateral nerve-preserving and nonpreserving treatments. 63

ACK N OWLED G M ENTS
This research was supported by the Ministry of Health, Labor, and Welfare KAKENHI Grant No. 21EA2004.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

E TH I C A L A PPROVA L
This research was supported by the Ethics Committee of Yokohama City University Medical Center.

H U M A N/A N I M A L R I G HT S S TATE M E NT S A N D I N FO R M E D CO N S E NT
This article does not contain any studies with human and animal subjects performed by any of the authors.